Functional consequences of novel connexin 26 mutations associated with hereditary hearing loss.
In a study of 530 individuals with non-syndromic, sensorineural hearing loss, we identified 18 mutations at connexin 26 (Cx26), four of which are novel (-23G>T, I33T, 377_383dupTCCGCAT, W172R) and the remaining 14 (ivs1+1G>A, M1V, 35delG, W24X, I35S, V37I, R75W, W77X, 312del14, E120del, Q124X, Y136X, R143W, R184P) being mutations previously described. To gain insight into functional consequences of these mutations, cellular localization of the mutant proteins and their ability to permit lucifer yellow transfer between cells was studied in seven of them (W24X, I33T, I35S, R75W, E120del, W172R and R184P). I35S and R184P showed impaired trafficking of the protein to the plasma membrane. I33T, R75W, E120del and W172R showed predominantly membrane localization but did not form functional gap junction channels. Surprisingly, W24X, a protein-truncating mutation, apparently permits formation of a full-length protein, perhaps due to a stop codon read-through mechanism. These results provide further evidence that Cx26 mutations affect gap junction activity by mis-regulation at multiple levels.
Mani
Ram Shankar
RS
Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India.
Ganapathy
Aparna
A
Jalvi
Rajeev
R
Srikumari Srisailapathy
C R
CR
Malhotra
Vikas
V
Chadha
Shelly
S
Agarwal
Arun
A
Ramesh
Arabandi
A
Rangasayee
Raghunath Rao
RR
Anand
Anuranjan
A
D000072259:Connexin 26; D017630:Connexins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism; D006367:HeLa Cells; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation
D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26